High-affinity GABA uptake in retinal glial (Muller) cells of the guinea pig: Electrophysiological characterization, immunohistochemical localization, and modeling of efficiency

Glial cells may act as important modulators of neuronal information processing, in particular, via fast uptake of neuronally released transmitters. Here, we characterize the electrogenic gamma-aminobutyric acid (GABA) transporters present in the plasma membranes of Muller (glial) cells of the guinea pig retina and present an estimate of their functional efficiency. The GABA-evoked whole-cell currents are voltage-dependent, with increasing amplitudes and decreasing affinity constants at more negative membrane potentials. The transmembranal GABA transport is concentration-dependent, with near-maximal currents at 100 muM GABA, and is dependent on extracellular sodium and chloride ions; the stoichiometry is 1 GABA/2 Na+/1 Cl-. Immunohistochemical labeling and whole-cell voltage-clamp records reveal that Muller cells express both GAT-1 and GAT-3 (but not GAT-2), and that the transporter proteins are expressed predominantly at plasma membrane sites that, in situ, are localized in the outer retina where GABA uptake is performed exclusively by Muller cells. When extracellular GABA enters the cell interior, it evokes, via activation of the GABA transaminase, an NAD(P)H fluorescence signal selectively in the distal region of the Muller cells where their mitochondria are located. Using our experimental data, we simulated the GABA clearance from the extracellular space surrounding one Muller cell; these estimates show that a pulse of 100 muM extracellular GABA is fully cleared after 70 ms. It is suggested that Muller cells may be involved in the regulation of GABAergic transmission within the retina by providing a fast termination of GABAergic signaling via their highly efficient GABA uptake.